The major objective of this research program is to gain new insights into the molecular and cell biological mechanisms underlying the production and actions of insulin and related peptide hormones of the islets of Langerhans, including their genetic basis, evolutionary origins, and disorders in these processes, which may contribute to the pathophysiology of diabetes and/or other diseases. New projects and extensions of previous work are proposed as follows: (1) Studies on prohormone convertases PC1/PC3 (SPC3) and PC2 (SPC2), including further characterization of neuropeptide processing defects in mice with targeted disruptions of the PC1/PC3 and PC2 genes individually or in various crosses, (2) Studies on the role of the neuroendocrine protein proSAAS in normal proinsulin processing and on the mechanisms underlying ACTH hypersecretion in 7B2 null mice, (3) Studies on convertase subdomain structure and on transcriptional regulation of the PC 1/PC3 and PC2 genes, (4) Studies on prohormone structure in relation to their processing by convertases, (5) New studies on the identification and characterization of unique beta and alpha cell proteins and their roles in glucagon and insulin production and secretion, (6) Further studies on evolution of insulin and insulin/IGF receptor signaling systems, and (7) New studies to characterize the temporal course of changes in hepatic gene expression in diabetic animals in response to insulin. These studies should all contribute to improving our understanding of the genetic, evolutionary, and molecular biological mechanisms underlying islet hormone production and action and should contribute to a better understanding of the pathophysiology of diabetes.